(1) PURPOSE - The purpose of the project is to evaluate mechanisms and related treatment approaches in chronic traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) using a mouse model. The three goals of this project are: 1) To determine the effects of chronic TBI and PTSD on memory and fear extinction learning. 2) To examine the effects of chronic TBI and PTSD on neuroinflammation, DAI, glia reactivity and dendritic spine morphology in PFC, HIPP and BLA regions; to examine the relationship between brain and behavioral changes. 3) To examine the effects of valproate (VPA) on memory and fear extinction and neurobiological changes in chronic TBI/PTSD. (2) BACKGROUND- (a) Scientific Rationale- TBI and PTSD have become the signature injuries from OEF/OIF war zones. Focal and diffuse brain injury occurs in TBI and this damage contributes to the associated neurocognitive and behavioral deficits. This proposed study comprehensively examines the effects of combined TBI and PTSD on axonal injury, neuroinflammation, and dendritic plasticity. Based on the research literature, we hypothesize that pharmacological treatment with VPA will enhance fear extinction learning and spatial memory and promote neural restoration in models of TBI and PTSD. (b) How this Research will Advance Knowledge in Rehabilitation Research - By increasing our understanding of the mechanisms and sequelae of brain injury and co-existing fear conditioning in animal models, we can examine potential biomarkers and screen candidate treatment approaches for humans with TBI/PTSD. (c) Significance of the Research and How it Relates to RR&D Priority Areas - The research relates to the RR&D Priority Area of Chronic Traumatic Brain Injury. Using a model of chronic TBI and PTSD is of critical importance for understanding brain and behavioral mechanisms and for the development of effective treatments for veterans. (d) Direct Benefits and Quality of Services - This study examines the effects of TBI and PTSD that have been sustained by many OIF/OEF veterans and will examine biomarkers for these conditions that can be then tested in humans. After testing in this model, the clinically available agent VPA can be carefully developed in studies for its pro-cognitive and fear extinction enhancing effects for veterans with TBI and/or PTSD. (3) EXPECTED OUTCOMES OR PRODUCTS - The first outcome of this study is to demonstrate that FPI and coexisting fear conditioning (FC) in mice impair long-term memory and extinction learning; these effects are associated with reductions in dendritic morphology in PFC, HIPP, and BLA. The second outcome is to show that the cognitive and fear extinction impairments in the TBI/PTSD model are associated with axonal injury, glial reactivity, and neuroinflammation in PFC, HIPP and BLA. The third outcome is to demonstrate that VPA treatment reverses spatial memory and fear extinction deficits in this model and reduces these neurobiological changes at 6 and 12 months post-injury. Additionally, we will demonstrate that administration of VPA from injectable gelatin delivered to the FPI injury site enhances cognition and reverses neurobiological effects. (4) METHODS AND RESEARCH PLAN - Male C57BL/6 mice are used because of their demonstrated utility in our FPI and FC model. Our FPI model uses a moderate level of percussive force to produce long-term brain injury. FPI mice will undergo cued FC procedures to produce a comorbid TBI/PTSD model. Behavioral testing is performed in FPI/FC mice using Morris Water Maze memory testing and fear extinction procedures. Brains are harvested from mice to measure changes in PFC, HIPP, and BLA using quantitative immunohistochemistry for axonal injury (as measured by ?-APP), neuroinflammation (as measured by IL-6 and GFAP) and dendritic plasticity (Golgi-Cox staining). In our FPI/FC model, we will test the effects of parenteral treatment with VPA at two separate chronic time points at 6 and 12 months. We will also pilot an approach using a biomaterial matrix for direct and continuous VPA administration at the TBI injury site.